The Bcl-2 family of proteins are key regulators of mitochondria-dependent apoptosis in nucleated cells and includes both anti-apoptotic (Bcl-xL, Bcl-2, Bcl-w, A1, Mcl-1) and proapoptotic (Bak, Bax, Bid, Bim, Bad, Bik, Bmf, Noxa, Puma) members. Generally, the expression of Bcl-2 protein is associated with many physiologic functions, including the inhibition of apoptosis in the body, in some cases resulting in proliferation of cells affected by the Bcl-2 inhibition. As such, inhibition of Bcl-2 protein may reduce cell proliferation, leading to improved outcomes related to the treatment and prevention of cancer.
Anti-apoptotic Bcl-2 proteins are associated with a number of diseases. Bcl-2 proteins may be involved bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, and the like. Additionally, Bcl-2 may be involved in immune and auto-immune diseases, as well as arthritis. Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system.
There is a continuing need in the therapeutic arts for compounds that inhibit the activity of anti-apoptotic Bcl-2 proteins.